D-serine is a naturally occurring amino acid and one of a class of amino acids that is known to be useful for treatment of neuropsychiatric disorder but which may cause nephrotoxicity when administered to rodents. In the brain, D-serine serves as a modulator of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Deficiencies of D-serine or of NMDA neurotransmission may contribute to the pathophysiology of multiple neuropsychiatric disorders including schizophrenia, Alzheimers disease, attention deficit hyperactivity disorder, autism, depression, and movement disorders (Javitt 2000; Tsai 2001). It has been proposed therefore that oral administration of D-serine at doses of 1 mg-100 g may serve as a novel treatment for these disorders. Clinical use of D-serine and of similar D-amino acids is potentially limited by concerns regarding renal toxicity, which has been observed in rodent species, especially in the rat. Thus, compounds are needed that prevent nephrotoxicity when given orally along with D-serine.
The ability of D-serine to induce renal injury in rats is reviewed by (Kaltenbach et al 1979). D-serine induced nephrotoxicity has been demonstrated since at least 1942, when it was noted an injurious action of DL-serine administered by stomach tube in rats maintained on a synthetic deficient in protrain and in B vitamins. Subsequent studies demonstrated that administration of 100 mg DL-serine induced acute renal necrosis at the junction of the renal cortex and medulla which was observed when serine was added to either stock diet or diet deficient in B vitamins. Lesions were consistently produced reliable with doses as small as 5 mg D-serine per 100 g. Despite intensive investigation, the mechanism by which orally administered D-serine induces nephrotoxicity remains an area of active research.
Nephrotoxicity induced by D-serine and other related amino acids is characterized by corticomedullary pathology, such as necrosis of the straight segment of the proximal tubule in the rat kidney following oral or intravenous administration. Severity of nephrotoxicity can be monitored by assessment of serum levels of creatanine and BUN (Orozco-Ibarra et al 2007). Similar nephrotoxicity can be induced by compounds structurally related to D-serine, including D-2,3-aminopropionic acid (DAPA) (Kaltenbach et al 1979).
Wachstein et al. investigated the ability of various compounds to reverse the effects of orally administered DL-serine (100 mg) as discussed by Kaltenbach et al., (Kaltenbach et al 1982). In all cases, test compounds were administered either subcutaneously or intramuscularly. These studies showed that nephrotoxic effects of DL-serine could be blocked by either DL-methionine or glutathione (GSH) when co-injected with D-serine in rats protects against the nephrotoxicity. Other compounds showing partial or full prevention of toxicity included glycine, DL-threonine, glycolic acid and sodium lactate. Several other compounds, however, were relatively ineffective including L-cysteine, sodium thioglycollate, 2,3 dithiopropanol (BAL), DL-alpha-alanine, L-histidine, L-arginine, DL-valine, butyric acid, D-glucose, sodium chloride, and sodium acetate. It was hypothesized that beneficial effects of these compounds were due to suppression of tubular reabsorption of the D-isomer.
Subsequent studies demonstrated significant protective effects of D-alanine, D-threonine, D-homoserine, DL-alpha-methylserine, beta-hydroxy-DL-leucine, and alpha-aminoisobutryic acid. As in Wachstein, all compounds were administered by injection prior to D-serine administration (Kaltenbach et al 1982). More recently, protective effects of alpha-aminoisobutyric acid (AIB) have been confirmed. It is hypothesized that this compound prevents uptake of D-serine into renal tubular cells, thereby limiting its nephrotoxic effects (Krug et al 2007).
In general, nephrotoxic effects of D-serine are considered to result from its metabolism by D-aminoacid oxidase (DAAO), which liberates reactive oxygen species such as peroxide (Krug et al 2007; Maekawa et al 2005; Williams and Lock 2005). This theory is supported by the observation that D-serine is not nephrotoxic is rats lacking-DAAO (Maekawa et al 2005), and that toxicity can be prevented by intrarenal injection of equimolar glutathione with D-serine (Krug et al 2007) or by intraperitoneal administration of large doses of sodium benzoate (Williams and Lock 2005). However, this theory is challenged by a recent study that failed to detect increased reactive oxygen species or peroxidation markers in rat kidney following D-serine injection. Further, several compounds with an antioxidant effect failed to prevent D-serine nephrotoxicity. (Orozco-Ibarra et al 2007). Therefore, not only can it be concluded from this reference that oxidative stress alone may be an insufficient model for nephrotoxicity, but this reference also constitutes a clear teaching away from the discovery of the present invention that in fact certain antioxidants when administered together with a D-amino acid are effective for reducing the risk of nephrotoxicity.